A. Background

Description

Vitamin A is a general term that refers
to fat-soluble compounds that are similar in structure and biologic
activity to retinol. Vitamin A also refers to dietary precursors
of vitamin A (6,11). The precursors of vitamin A (retinol) are
the carotenoids (most commonly beta-carotene). The term retinoid
refers to any compound that is structurally similar to retinal
(aldehyde), retinol (alcohol), or any other substance that exhibits
vitamin A activity (1). Retinoic acid, which is a metabolite
of retinal (6), is such a substance that is often studied. Synthetic
compounds within the vitamin A family have similar structures
as the natural form, but may have few or no functions that the
natural vitamin posses (11). Most compounds within the vitamin
A family are soluble in fat and essential to numerous processes
within the body. There have been several water-soluble retinoids,
extracted from plasma, bile, and other tissue (11). For the purposes
of this literature review, any discussion of vitamin A will focus
on those retinoids with fat-soluble properties. The main discussion
will involve retinol. Retinol is chemically a "pale yellow
crystalline solid" (6). The solid and its metabolites exist
in nature as various isomers. The biologic metabolites of retinol
are unique in that, they contain five conjugated double bonds
within their six-carbon ring (B-ionone) and isoform specific
side chains (11). The double bonds contribute special properties;
for example, the double bonding in retinol plays a unique role
in multiple vision processes, which will be discussed in a subsequent
section of this review. As mentioned earlier, most retinoids
are soluble in organic solvents and fat. However, oxidation and
polymerization are all detrimental to retinoids; therefore, the
compounds must be protected from light, oxygen and high temperature.

Dietary Function

Vitamin A is essential for numerous intrinsic
processes. The most well-known and understood process is that
of vision. The 11-cis retinal form of vitamin A is essential
for the neural transmission of light into vision (11). Epithelial
cells are highly dependent on retinoic acid and are commonly
used to treat a variety of skin diseases. A developing fetus
is also highly dependent on retinoic acid, as it is essential
to the growth of the eyes, lungs, ears and heart (6). The retinoids
are not only the most active form of vitamin A, but also a current
area of interest to many scientists. The role of vitamin A as
an antioxidant is debatable. Vitamin A has been shown to possibly
have some antioxidant characteristics. However, the carotenoids
such as beta-carotene have in recent years received more attention
from the scientific community because of the harmful role they
may play as pro-oxidants (14). A great deal more research is
needed that addresses the role of vitamin A as an antioxidant
to determine the exact role the vitamin and precursors play.

Sources

Retinol, the active form of vitamin A, is
rarely found in foods. Instead, precursors to retinol, fatty
acid retinyl esters, are found in the human diet. The esters
are commonly found in foods of animal origin, such as egg yolks,
liver, fish oil, whole milk and butter (6). Plants can synthesize
the carotenoids, but cannot convert them to retinoids; this process
occurs in the human body (11). The carotenoids are red, yellow,
and orange in color and substantial in number (over 400 types).
It is estimated that only 10% of the pigments have "vitamin
A activity", with beta-carotene having the greatest activity,
followed by the alpha and gamma forms (6). Fruits and vegetables
that appear bright orange or yellow in color are usually high
in carotenoids. All green vegetables also contain substantial
amounts of carotenoids, but the orange or yellow color is masked
by chlorophyll (6). The wide variety of vitamin A precursors
allow for adequate amounts of the vitamin in all diet types.

B. Metabolism

Absorption and Bioavailability

Seventy to ninety percent of vitamin A from
the diet is absorbed in the intestine. The efficiency of absorption
for vitamin A continues to be high (60-80%) as intake continues
to increase. Greater than 90% of the retinol store within the
body enters as retinyl esters that are subsequently found within
the lipid portion of the chylomicron (11). Absorption of vitamin
A is very rapid, with maximum absorption occurring two to six
hours after digestion (11). Within the intestinal lumen, the
vitamin is incorporated into a micelle and absorbed across the
brush border into the enterocytes. Within the enterocyte, precursors
of vitamin A (carotenoids) are converted to active forms of the
vitamin. The newly formed products and additional precursors
are then packaged into chylomicrons and readied for transport
throughout the body (6).

Transport

After leaving the enterocytes, chylomicronswhich
carry retinyl esters, carotenoids, and unesterfired retinol along
with triglycerides, are circulated first through the lymphatic
system and then through the general circulation. Upon arriving
at extra-hepatic cells, chylomicrons release triglycerides, however,
vitamin A remains within the chylomicron. The vitamin A is then
incorporated into a chylomicron remnant (6). The chylomicron
remnant then travels back to the liver, where it is taken up
and further metabolized or stored. When needed, retinol is mobilized
from the liver and requires the use of a carrier for transport
through the blood. Retinol-binding protein (RBP) is the specific
carrier used to transport all-trans retinol in the plasma. The
all-trans isoform accounts for more than 90% of all plasma vitamin
A (11). This specific carrier is manufactured and secreted by
the parenchymal cells of the liver (6,11). Each mole of retinol
released binds equivocally with RBP to form holo-RBP. This compound
then binds with a molecule of transthyretin (TTR), formerly known
as prealbumin. This newly formed retinol-RBP-TTR complex is not
filtered by the glomerulus, but instead, freely circulates throughout
the plasma. Tissues are then able to take the retinol up as needed
via cellular retinoid-binding protein (11). Retinoic acid is
believed to be manufactured by the cells as needed. Therefore,
transport of retinoic acid is likely not substantial. Instead,
the cell possesses intra-cellular proteins that regulate the
amount of retinoic acid produced. The proteins also help to determine
the intracellular usage of retinoic acid (6).

Storage

Approximately, 50 to 85% of the total body
retinol are stored in the liver when vitamin A status is adequate
(11). Retinol returning to the liver is re-esterfied before storage.
Because of this, over 90% of the retinol is stored in the form
of retinyl esters. The retinol is stored in hepatic stellate
(star-shaped) cells along with droplets of lipid (6,11). Thus
constitutes the fat-soluble property of vitamin A. The size of
stellate cells increases linearly with increasing retinol levels.
Once hepatic stellate cells are saturated with all the retinol
they can hold, hypervitaminosis can result. (11). The precursor
to vitamin A, beta-carotene, can be stored in adipose cells of
fat depots throughout the body (2). To date, the only side effect
of excess beta-carotene supplementation appears to be yellowing
of the skin. Serum levels of beta-carotene are an indicator of
recent intake and not body stores (6).

Excretion

The kidneys are the main paths of RBP and
retinol excretion from the body. This is achieved mainly via
renal catabolism and glomerular filtration (11). Those persons
suffering from renal disease often experience elevated serum
levels of RBP and retinol and therefore, must be more aware of
vitamin A toxicity.

Physiological
Role

As previously mentioned, vitamin A is essential
to vision. Within the photoreceptor cells of the retina are the
rods, which detect small amounts of light and are specialized
for motion detection and vision in dim light, and the cones that
are specialized for color vision in bright light (11). Both rods
and cones posses specialized outer segment disks that contain
high amounts of rhodopsin and iodopsin respectively. These compounds
are often referred to as the "visual pigment" (11).
Photoreceptor cells detect light and undergo a series of reactions,
which send signals to the brain, where they are deciphered as
a particular visual image. A second very important function of
vitamin A involves retinoic acid. Acting as a hormone, retinoic
acid first binds to retinoic acid receptors. The receptors then
interact with specific nucleotide sequences of DNA. The interaction
directly affects gene expression and transcription, which in
turn, control cellular development and body processes (6). For
example, epithelial cells depend on retinoic acid for structural
and functional maintenance. This role of vitamin A is important
for growth mechanisms in a manner that is not completely understood
(6). Retinoic acid is especially important in heart, eye, lung
and ear development (11). The development of gap junctions between
cells is also affected by retinoic acid (6). Besides the previously
mentioned functions, vitamin A plays a role in numerous other
processes. Vitamin A is thought to play a key role in glycoprotein
synthesis. Once formed, glycoproteins are important in multiple
cellular processes including: communication, recognition, adhesion,
and aggregation. Reproductive processes, bone development, along
with maintenance, and immune system function (6,11) are dependent
upon different isoforms of vitamin A. Retinoids are most commonly
used in the treatment of skin diseases. The role the retinoids
play in epithelial cell formation is very important in the treatment
of skin cancer, acne, and acne-related diseases (11). Vitamin
A also has antioxidant properties. However, beta-carotene has
been noted as having pro-oxidant properties. Despite these discrepancies,
vitamin A is known to help repair damaged tissue and therefore
may be beneficial in counter-acting free radical damage (11).

C. Daily Reference
Intakes (DRI)

Current DRI

The Recommended Dietary Allowance (RDA)
established in 1980 for vitamin A was set at 800-ug retinol equivalent
(RE) for adult women and 1000 ug (1mg) retinol equivalent (RE)
for adult men (6). It should be noted that 1 RE of vitamin A
is equal to 3.33 IU of the vitamin. The levels (RDA) were not
changed in 1989 when the RDAs were revised (6,11). One RE is
equivalent to 1 ug of all-trans retinol, or 6 ug of all-trans
beta-carotene (6). The RDA was based on the amount of vitamin
needed to reverse night-blindness in vitamin A deficient subjects.
The RDA has also been based on the amount needed to raise the
plasma vitamin A levels to normal in depleted subjects. Starting
in 2000, Dietary Reference Intakes (DRI) were developed to replace
the RDA. A DRI for vitamin was not be established. The DRI incorporates
a safety ceiling into the recommendation, however, due to a lack
of evidence, a safe upper limit could not established. The absence
of a safe upper limit plus the numerous carotenoids has led the
National Academy of Sciences to not establish a DRI at this time.
The RDA is the current dietary guideline being used in place
of the DRI. For men the RDA is 1000 mg of retinol equivalents
(RE) and for women the RDA currently stands at 800 mg RE (10).

Deficiency

Deficiency of vitamin A is very rare in
the United States, unless confounding malabsorption conditions
such as steatorrhea, or diseases of the liver, pancreas, or gallbladder
are present. In contrast, vitamin A deficiency is prominent in
young children (<5 years old) living in third world countries
(6,11). At birth, many neonates experience low plasma vitamin
A content, but the levels are corrected with a diet sufficient
in vitamin A (6). Symptoms of vitamin A deficiency include metaplasia
(changing of normal tissue into abnormal tissue), poor growth,
xerophthalmia (dry corneas), and keratinization of epithelial
cells resulting in a loss of differentiation (6,11). If vitamin
A deficiency has not been chronic leading to permanent debilitation,
the symptoms can often be reversed through supplementation.

Toxicity

The use of acne medicines (i.e. Acutane)
has led to birth defects and even death (11) in children born
to mothers using these compounds (6). This has helped make the
public more aware of the toxic properties of vitamin A. In adults,
a condition known as hypervitaminosis exhibits itself after chronic
ingestion of the vitamin in doses that are ten times the RDA
(10 mg RE). Symptoms of vitamin A toxicity include: anorexia,
headache, bone and muscle pain, vomiting, alopecia, liver damage,
and coma. These symptoms slowly reside as vitamin A intake levels
are reduced (6,11). To date, the only side effect of excess beta-carotene
has been yellowing of the skin, most commonly in the fatty areas
of the hands and palms. The yellowing disappears as beta-carotene
intake decreases. This commonly ingested dietary precursor to
vitamin A has yet to exhibit any signs of toxicity even at levels
as high as 180 mg per day (6). Researchers believe that the presentation
of unbound retinol to the cell is a major factor in toxicity.
Excessive intakes of vitamin A saturate RBP and instead of retinol
being transferred bound to RBP, it is transferred to the tissue
via plasma lipoproteins. When retinol reaches the tissue by a
carrier other than RBP, it is hypothesized that the retinol is
released and causes toxic side effects (6).

D. Vitamin A
and Exercise

Effects of Exercise on Vitamin A Requirements

Data addressing vitamin A and any aspect
of exercise are lacking at best. A literature review done by
Stacewicz-Sapuntzakis (12) reports that there has been essentially
no evidence to suggest that the vitamin A needs of athletes and
exercisers are increased above those of sedentary individuals.
For example, the author reports that cyclists in the Tour de
France were found to consume adequate amounts of the vitamin
during the race. The studies that have been performed have failed
to account for training patterns or specify the percentages of
vitamin A coming from meat and plant sources respectively. This
has led to difficulty determining the carotenoid intake of individuals
in these studies (12). In contrast, serum levels of retinol and
beta-carotene have been studied in national teams from West Germany.
The athletes tested came from a variety of sports: marathon runners,
weightlifters, swimmers, and cyclists. The research showed that
none of the athletes exhibited depressed retinol levels. Beta-carotene
levels were distributed over a wide range of values (14.0-122.5
ug/dl). Results show that, although there was a wide range of
intakes, none of the athletes were deficient in beta-carotene
(12). Many athletes looking for a competitive edge will increase
their daily vitamin intake. This has led to widespread vitamin
A abuse among athletes. Toxic side effects from vitamin A consumption
have so far only been documented in one subject. The subject,
a high school soccer player, whose daily, two-month consumption
of vitamin A was 100,000 IU vitamin A per day suffered from excessive
leg pain (5).

The carotenoids, specifically beta-carotene
has been shown to possess antioxidant properties. This precursor
of vitamin A is considered the most efficient "quencher"
of singlet oxygen (6). The antioxidant properties may actually
be detrimental to the body however. The carotenoids may undergo
oxidation, leaving byproducts in the lungs and arterial blood.
This can result in additional oxidative damage and tumor growth
in smokers and those exposed to either second-hand smoke or automobile
fumes. Limited studies have been performed addressing the possible
role of beta-carotene plays in prevention of muscle damage. Unfortunately
the studies included vitamin A as part of antioxidant cocktail
mixture (8,9). In a study by Kanter et al. (9), the antioxidant
cocktails lowered markers of oxidative stress during exercise,
but not before or after the exercise bout. Use of the cocktail
makes it virtually impossible to assess the effects of vitamin
A on lipid oxidation. The evidence addressing beta-carotene has
actually shown detrimental effects in some subjects. This body
of inconclusive and somewhat detrimental evidence has led to
the recommendation that those who exercise should refrain from
beta-carotene supplementation (14).

Vitamin A in
Exercise Recovery

The role vitamin A plays in exercise recovery
has yet to be determined. There is an obvious lack of credible
evidence suggesting vitamin A plays a role in enhancing exercise
performance or preventing lipid peroxidation. However, due to
the ability of vitamin to repair muscle tissue damage (12) the
vitamin may aid in recovery. This is strictly a hypothesis, as
the possibility has yet to be proven or even investigated. In
order to better understand the role of vitamin A in exercise
recovery, studies need to be designed that address the issue.

E. Summary &
Current Recommendations

The level of vitamin A intake in all persons,
regardless of exercise seems to be more than adequate. This is
mainly due to the wide variety of foods that contain vitamin
A and its precursors. Vitamin A research is a very tedious process
that has little room for error. To date, no research has conclusively
shown that vitamin A alone (not part of a cocktail mixture) in
any way improves exercise capacity, recovery, or lipid peroxidation.
Furthermore, vitamin A can be toxic and beta-carotene has pro-oxidant
capabilities. In summary, any supplementation of vitamin A for
improvements in exercise is unwarranted, dangerous, and may involve
risks.

Volpe, S. Vitamins and minerals for active
people. In: Sports Nutrition: A guide for the professional working
with active people. Edited by C.A. Rosenbloom. The American Dietetic
Association: Chicago, 2000, p. 68-69.